BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans.
BLVRB redox mutation defines heme degradation in a metabolic pathway of enhanced thrombopoiesis in humans.
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DOI：
10.1182/blood-2016-02-696997
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发表时间：
2016-08
期刊：
影响因子：
20.3
通讯作者：
Song Wu;Zongdong Li;D. Gnatenko;Beibei Zhang;Lu Zhao;Lisa E Malone;N. Markova;T. Mantle;N. M. Nesbitt;W. Bahou
中科院分区：
文献类型：
--
作者：
Song Wu;Zongdong Li;D. Gnatenko;Beibei Zhang;Lu Zhao;Lisa E Malone;N. Markova;T. Mantle;N. M. Nesbitt;W. Bahou
人类血细胞计数严格维持在狭窄的生理范围内，主要由调节多谱系造血规范的细胞因子整合信号传导和转录回路控制。影响血细胞产生的已知遗传位点占血小板和红细胞变异性的<10%，并且血小板生成素/细胞性骨髓增殖性白血病病毒配体对于确定的血小板生成是可有可无的，这表明根本上重要的修饰位点仍未阐明。在这项研究中，血小板转录组测序和扩展的血小板增多症队列分析确定了与血小板生成增强的克隆性和非克隆性疾病相关的单一功能丧失突变 (BLVRB(S111L))。底物/辅因子 [α/β 二核苷酸 NAD(P)H] 结合折叠内包含的 BLVRB(S111L) 是一种功能缺陷的氧化还原偶联剂，使用黄素和胆绿素 (BV) IXβ 四吡咯，导致活性氧过度积累，作为推定的代谢信号，导致造血谱系差异 承诺和增强的血小板生成。这些数据定义了 BLVRB 的第一个生理相关功能，并暗示其活性和/或血红素调节的 BV 四吡咯在控制终末巨核细胞生成的独特氧化还原调节生物能途径中；这些观察结果还确定了一个机械限制的药物靶点，保留了增强人类血小板计数的潜力。
Human blood cell counts are tightly maintained within narrow physiologic ranges, largely controlled by cytokine-integrated signaling and transcriptional circuits that regulate multilineage hematopoietic specification. Known genetic loci influencing blood cell production account for <10% of platelet and red blood cell variability, and thrombopoietin/cellular myeloproliferative leukemia virus liganding is dispensable for definitive thrombopoiesis, establishing that fundamentally important modifier loci remain unelucidated. In this study, platelet transcriptome sequencing and extended thrombocytosis cohort analyses identified a single loss-of-function mutation (BLVRB(S111L)) causally associated with clonal and nonclonal disorders of enhanced platelet production. BLVRB(S111L) encompassed within the substrate/cofactor [α/β dinucleotide NAD(P)H] binding fold is a functionally defective redox coupler using flavin and biliverdin (BV) IXβ tetrapyrrole(s) and results in exaggerated reactive oxygen species accumulation as a putative metabolic signal leading to differential hematopoietic lineage commitment and enhanced thrombopoiesis. These data define the first physiologically relevant function of BLVRB and implicate its activity and/or heme-regulated BV tetrapyrrole(s) in a unique redox-regulated bioenergetic pathway governing terminal megakaryocytopoiesis; these observations also define a mechanistically restricted drug target retaining potential for enhancing human platelet counts.